Thrombocythemia is a chronic disorder associated with increased or abnormal production of blood platelets. Since platelets are involved in blood clotting, their abnormal production can result in the inappropriate formation of blood clots or in bleeding, with the consequence that patients' risk of gastrointestinal bleeding, heart attack and stroke is increased.
Anagrelide is a quinazoline derivative phosphodiesterase inhibitor used for the treatment of essential thrombocythemia and various other myeloproliferative disorders. Anagrelide was approved and launched in 1997 for the treatment of essential thrombocythemia in the US and Canada. In December 1998, the US FDA approved an expanded label for anagrelide—specifically, for the treatment of patients with thrombocythemia secondary to myeloproliferative disorders, including polycythemia vera (PV) and chronic myelogenous leukemia (CML).
A compound encompassed by the present invention is 3-hydroxyanagrelide. This is a metabolite of anagrelide (see, for example, U.S. patent application Ser. No. 10/762,566 published as U.S. Pub. No. 20040209907).
Various metabolites of anagrelide have been studied in the literature: Erusalimsky et al. (2002) Is the platelet lowering activity of anagrelide mediated by its major metabolite 2-amino-5,6-dichloro-3,4-dihydroquinazoline (RL603)? Exp Hematol. 30:625-7; Lane et al. (2001) Anagrelide metabolite induces thrombocytopenia in mice by inhibiting megakaryocyte maturation without inducing platelet aggregation. Exp Hematol. 29:1417-241; and Gaver et al. (1981) Disposition of anagrelide, an inhibitor of platelet aggregation. Clin Pharmacol Ther. 29:381-6.
It is among the objects of the present invention to provide compounds related to anagrelide that may be used for treating thrombocythemia.